Division of Nephrology, Zhongshan Hospital Fudan University, Shanghai, China.
PLoS One. 2013 May 30;8(5):e64329. doi: 10.1371/journal.pone.0064329. Print 2013.
Aminoglycoside antibiotics, especially gentamicin, are widely used to treat Gram-negative infections due to their efficacy and low cost. Nevertheless the use of gentamicin is limited by its major side effect, nephrotoxicity. Xenon (Xe) provided substantial organoprotective effects in acute injury of the brain and the heart and protected against renal ischemic-reperfusion injury. In this study, we investigated whether xenon could protect against gentamicin-induced nephrotoxicity. Male Wistar rats were intermittently exposed to either 70% xenon or 70% nitrogen (N2) balanced with 30% oxygen before and during gentamicin administration at a dose of 100 mg/kg for 7 days to model gentamicin-induced kidney injury. We observed that intermittent exposure to Xe provided morphological and functional renoprotection, which was characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress, but not a reduction in inflammation. We also found that Xe pretreatment upregulated hypoxia-inducible factor 2α (HIF-2α) and its downstream effector vascular endothelial growth factor, but not HIF-1α. With regard to the three HIF prolyl hydroxylases, Xe pretreatment upregulated prolyl hydroxylase domain-containing protein-2 (PHD2), suppressed PHD1, and had no influence on PHD3 in the rat kidneys. Pretreatment with Xe also increased the expression of miR-21, a microRNA known to have anti-apoptotic effects. These results support Xe renoprotection against gentamicin-induced nephrotoxicity.
氨基糖苷类抗生素，特别是庆大霉素，由于其疗效好、成本低，被广泛用于治疗革兰氏阴性感染。然而，庆大霉素的使用受到其主要副作用肾毒性的限制。氙气（Xe）在脑和心脏的急性损伤以及肾缺血再灌注损伤中提供了大量的器官保护作用。在这项研究中，我们研究了氙气是否可以预防庆大霉素引起的肾毒性。雄性 Wistar 大鼠在庆大霉素（100mg/kg）给药前和给药期间，间歇性暴露于 70%氙气或 70%氮气（N2）与 30%氧气混合气体中，共 7 天，以模拟庆大霉素引起的肾损伤。我们观察到，间歇性暴露于 Xe 提供了形态和功能的肾保护，其特征是肾小管损伤、细胞凋亡和氧化应激的减弱，但没有减轻炎症。我们还发现，Xe 预处理上调了缺氧诱导因子 2α（HIF-2α）及其下游效应因子血管内皮生长因子，但没有上调 HIF-1α。对于三种 HIF 脯氨酰羟化酶，Xe 预处理上调了脯氨酰羟化酶结构域蛋白-2（PHD2），抑制了 PHD1，对大鼠肾脏中的 PHD3 没有影响。Xe 预处理还增加了 miR-21 的表达，miR-21 是一种已知具有抗细胞凋亡作用的 microRNA。这些结果支持 Xe 对庆大霉素引起的肾毒性的肾保护作用。
